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Genetic Determinants Underlying Rare Diseases Identified Using Next-Generation Sequencing Technologies

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Western University Scholarship@Western Electronic Thesis and Dissertation Repository 8-2-2018 1:30 PM Genetic determinants underlying rare diseases identified using next-generation sequencing technologies Rosettia Ho The University of Western Ontario Supervisor Hegele, Robert A. The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Rosettia Ho 2018 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Medical Genetics Commons Recommended Citation Ho, Rosettia, "Genetic determinants underlying rare diseases identified using next-generation sequencing technologies" (2018). Electronic Thesis and Dissertation Repository. 5497. https://ir.lib.uwo.ca/etd/5497 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Rare disorders affect less than one in 2000 individuals, placing a huge burden on individuals, families and the health care system. Gene discovery is the starting point in understanding the molecular mechanisms underlying these diseases. The advent of next- generation sequencing has accelerated discovery of disease-causing genetic variants and is showing numerous benefits for research and medicine. I describe the application of next-generation sequencing, namely LipidSeq™ ‒ a targeted resequencing panel for the identification of dyslipidemia-associated variants ‒ and whole-exome sequencing, to identify genetic determinants of several rare diseases. Utilization of next-generation sequencing plus associated bioinformatics led to the discovery of disease-associated variants for 71 patients with lipodystrophy, two with early-onset obesity, and families with brachydactyly, cerebral atrophy, microcephaly-ichthyosis, and widow’s peak syndrome. Understanding these variants and their contribution to disease can increase understanding of disease mechanisms and help with the development of therapeutic interventions in the future. i Keywords Next-generation sequencing; targeted sequencing; whole-exome sequencing; Mendelian disease; genetic disease; rare disease; metabolic disease; lipodystrophy; extreme early- onset obesity; brachydactyly; cerebral atrophy; CARE for RARE; FORGE Canada; autosomal recessive; autosomal dominant; variant discovery; copy-number variation ii Co-Authorship Statement Dr. Robert A. Hegele provided all the supervision and funding, and his input for the conceptualization, design and protocols of this Thesis project. Dr. Hegele also provided all lipodystrophy, two extreme early-onset obesity, and cerebral atrophy samples. Chapters 1, 3 and 4 contain modified text from a submitted manuscript entitled, “Whole- exome sequencing identifies a novel IHH insertion in an Ontario family with brachydactyly type A1”, co-authored by Adam D. McIntyre, Brooke A. Kennedy, and Dr. Robert A. Hegele. Dr. Hegele, Dr. Kathleen A. Hill and Dr. C. Anthony Rupar provided critical revision for all Chapters. Dr. Victoria M. Siu provided three of the extreme early-onset obesity samples discussed in the Thesis, and the CARE for RARE and FORGE Canada consortiums provided samples for the CARE for RARE/FORGE Canada projects. Dr. Siu, Dr. Rupar and Dr. Rana Chakrabarti provided clinical information, additional samples and support. Dr. Jian Wang, Dr. Henian Cao, and Adam D. McIntyre each contributed their technical expertise to the design of this Thesis project. More specifically, Dr. Wang helped with primer design and conceptualization, and greatly assisted with the validation of copy- number variation events, Dr. Cao performed all LipidSeq™ targeted sequencing, and Adam C. McIntyre provided clinical information and technical support. John F. Robinson provided assistance and support for each CARE for RARE and FORGE Canada project. Brooke A. Kennedy provided clinical information for the brachydactyly case. In addition to the co-authors listed above, several students were involved in the CARE for RARE and FORGE Canada projects. Calwing Liao provided expertise and technical support for the microcephaly-ichthyosis, heterotaxy, and widow’s peak cases; Cory Soininen worked on the dystonia case; Gagandeep Singh worked on sequence analysis for the craniorachischisis case; Jing (Tony) Yao worked on the craniosynostosis case; and Xingyu (Robin) Liu helped with the sequencing analysis of the cryptophthalmos case. iii Dedication In loving memory of my Grandma – thank you for supporting me, loving me unconditionally and raising me to be the person I am today. I love and miss you more than words can say. iv Acknowledgements The past few years in the Hegele lab have been some of the most enriching years of my life. I have learned more than I thought possible from extraordinary individuals and created great friendships with my exceptional colleagues. Here, I would like to acknowledge the fantastic individuals that made my Thesis such a rewarding experience. First and foremost, I would like to thank my supervisor, Dr. Rob Hegele, for his supervision, support and mentorship. You have been a guiding light throughout my entire Masters, and I will be forever grateful for the time I spent under your supervision. In addition to your knowledge, thank you for bringing me laughter on Friday afternoons, and sharing your love of dogs. Speaking on behalf of all the graduate students past-and- present and myself, we are so thankful for everything you do. Thank you for taking a chance on me in third year. It has been a privilege to be your student. To my advisory committee, Dr. Kathleen Hill and Dr. Tony Rupar, thank you for your outstanding mentorship. I am so appreciative of all the feedback and support you have provided, not only during committee meetings but elsewhere as well. An additional thank you to Dr. Hill for being so supportive these past few years. It has been an absolute honour to have you as an advisor for both my undergraduate and graduate Thesis projects. Thank you to Dr. Victoria Siu for being a mentor to me. It has been a pleasure to work with you on this Thesis project, and to volunteer in the clinic with you. Your wisdom and graciousness are inspiring. To the entirety of the Hegele lab, thank you so much for being such excellent colleagues and listening to me rant throughout my years in the lab. Thank you to Adam McIntyre for all your support throughout my Thesis – from helping me find charts, office supplies or DNA samples – you have been so helpful throughout it all. Thank you to John for your help along the way. Also, thank you so much to Dr. Henian Cao for all your technical assistance and mentorship. Furthermore, thank you, Dr. Jian Wang, not only for your v mentorship but also for recommending the best Chinese restaurants and being such a great colleague – I hope that one day we finally get our trio sequenced. To the Department of Biochemistry, thank you for providing administrative and research support. Thank you to Barb Green for being a friendly face in the department and providing administrative assistance. Thank you to the friends I have made along the way – Emily, Cal, Amy, Nadya, Freda – you are the best. Thank you so also to the brilliant Sali for your mentorship, kindness, and guidance. To my main pals – Alli, Jacqueline and Michael – thank you so much for being such remarkable human beings and for all the memories. I would not be where I am without you and your humour, laughter, and support of my eccentric personality. I look forward to staying in contact and watching you all succeed in the future. More specifically, Alli – thank you for being my twin. We are the same person and I would not have it any other way. I could not imagine having a better, more beautiful or generous neighbour than you. Jacqueline – you are an angel on earth. Thank you for your kindness and thoughtfulness; you inspire me every day. Thank you for being the light in the darkest of times. Michael – thank you for being such a great friend. You and I are two peas in a pod; if I had to choose anyone to be incarcerated with, it would be you. To my family – I love you with all my heart. Thank you to my Mom and Dad for your encouragement, support and unconditional love. I know how much you have sacrificed for Neuton and me. I could not imagine better, more generous, caring parents than you. To my sidekick Neuton (hey, brother!), you are not just my sibling but also my best friend. To Shirley, you are a sister to me, and I am so grateful for our lifelong relationship. Thank you, Neu and Shin, for keeping me young and fun and being there to talk to about anything. To my Grandma, I will cherish our memories forever. To Jayvee, thank you for opening my heart and coming into my life when I needed you the most. Lastly, to my partner Alex, thank you for indulging in Junior Chickens with me, going to every restaurant, letting me vent, and being there for the last six-and-a-half years and counting. You are the definition of a partner-in-crime, and I am so grateful for you. vi Table of Contents Abstract ........................................................................................................................................... i Keywords ........................................................................................................................................ii Co-Authorship Statement
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